Processes and intermediated for quinine, quinidine, isomers and derivatives thereof

ABSTRACT

The preparation of quinine, quinidine, isomers and derivatives thereof from the correspondingly substituted 4-methyl-quinoline and 1-acyl(or 1-H)-3-vinyl(or lower alkyl)-4-piperidine acetic acid esters (or acetaldehyde) through alternative series of reaction steps which comprise, condensation, halogenation, deacylation, reduction, cyclization and hydroxylation, is described. Also described is the preparation of 1-acyl(or 1-H)-3vinyl-4-piperidineacetic acids and esters theroef and 1-acyl-3vinyl-4-piperidineacetaldehyde utilizing the corresponding 7acyldecahydro-2H-pyrido(3,4-d)azepin-2-one, prepared from 2-acyl1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end products are useful as antimalarial and antiarrhythmic agents.

United States Patent [191 Gutzwiller et al.

[ Dec. 31, 11974 1 PROCESSES ANDINTERMEDIATED FOR QUININE, QUINIDINE, ISOMERS AND DERIVATIVES THEREOF [73] Assignee: Hoffman-La Roche Inc., Nutley,

[22] Filed: Aug. 1, 1973 [21] Appl. No.: 384,523

Related US. Application Data [60] Division of Ser. No. 212,774, Dec, 27, 1971, Pat. No. 3,772,302, which is a continuation-in-part of Ser. No. 104,784, Jan. 7, 1971, abandoned, which is a continuation-in-part of Ser. No. 837,354, June 27, 1969, abandoned, which is a continuation-in-part of Ser. No. 741,914, July 2, 1968, abandoned.

[52] 11.8. Cl "260/240 R, 424/258, 424/259, 260/293.53, 260/293.55, 260/293.77,

260/289 R [51] Int. Cl C091) 23/00 [58] Field of Search 260/240 R [56] References Cited UNITED STATES PATENTS 3,772,302 11/1973 Gutzwiller et al. 260/284 FOREIGN PATENTS OR APPLICATIONS 1,933,600 1/1970 Germany 260/240 R OTHER PUBLICATIONS Gopalchari, Chemical Abstracts, vol. 55, col. 27321, (1961), (abst. of article in J. Sci. Ind. Research, India, vol. 19C, pages 296 to 298, 1960).

Lyle et al., Tetrahedron Letters, No. 21, pages 13-71 to 1378, (1963).

Primary Examiner.lohn D. Randolph Attorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; William G. Isgro [5 7 ABSTRACT The preparation of quinine, quinidine, isomers and derivatives thereof from the correspondingly substituted 4-methyl-quinoline and I-acyl(or 1-I-I)-3-vinyl(or lower alky1)-4-piperidine acetic acid esters (or acetaldehyde) through alternative series of reaction steps which comprise, condensation, halogenation, deacylation, reduction, cyclization and hydroxylation, is described. Also described is the preparation of l-acy1(or 1-I-l)-3-viny1-4-piperidineacetic acids and esters theroef and 1-acy1-3-vinyl-4-piperidineacetaldehyde utilizing the corresponding 7-acyldecahydro-2I-I- pyrido[3,4-d1azepin-2-one, prepared from 2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end products are useful as antimalarial and antiarrhythmic agents.

3 Claims, No Drawings PROCESSES AND INTERMEDIATEI) FOR QUININE, QUINIDINE, ISOMERS AND DERIVATIVES THEREOF This is a division, of application Ser. No. 212,744 filed 12/27/71, now U.S. Pat. No. 3,772,302 issued Nov. 13, 1973, which in turn is a C.I.P. of Ser. No. 104,784, filed 1/7/71, now abandoned, which is a C.I,P. of Ser. No. 837,354, filed 6/27/69, now abandoned, which is a C.l.P. of Ser. No. 741,914, filed 7/2/68, now abandoned.

BRIEF SUMMARY OF THE INVENTION The invention relates to a process for preparing quinine, quinidine, isomers and derivatives thereof which comprises: p

a. condensing the correspondingly substituted 4- methylquinoline with racemic or optically active cis or trans 1-acyl(or 1-H)-3-vinyl(or lower alkyl)-4- piperidineacetic acid ester to yield the corresponding racemic or optically active cis or trans 4-{3-[1-acyl(or l-H)-3-vinyl(or lower alkyl)-4-piperidyl]-2-oxopropyl}quinoline;

b. deacylating, if necessary, and reducing the'product of step (a) to yield the corresponding racemic or optically active epimeric 4-{cis or trans-3-[3-vinyl(or lower alkyl)-4-piperidyl]-2-hydroxypropyl}quinolines. If desired, this reaction product can be acylated to yield racemic or optically active epimeric 4-{cis or trans-3-[3- vinyl(or lower alkyl)-4-piperidyl]-2- acyloxypropyl}quinolines or dehydrated to yield racemic or optically active cis or trans 4-{cis or trans 3-[3- vinyl(or lower alkyl)-4- piperidyl1prop-1-enyl}quinolines;

0. an alternate process comprises condensing the correspondingly substituted 4-methylquinoline with racemic or optically active cis or trans l-acyl-3-vinyl(or lower alkyl)-4-piperidineacetaldehyde to yield the corresponding racemic or optically active epimeric 4-{cis or trans-3-Il-acyl-3-vinyl(or lower aklyl)-4-piperidyl]- 2g-hydroxypropyl}quinolines, and deacylating this reaction product to yield the corresponding racemic or optically active epimeric 4-{cis or trans-3-[3-vinyl (or lower alkyl)-4-piperidyl]-2-hydroxypropyl}quinolines;

(I. cyclizing the hydroxy, acyloxy or prop-l-enyl quinoline product of step (b) or (c) to yield the corresponding racemic or optically active 4-{a[5-vinyl(or lower alkyl)-2-quinuclidinyl]-methyl }quinoline, epimeric in positions 2 and 5;

e. hydroxylating the product of step (d) to yield the corresponding racemic or optically active a- [5-vinyl(or lower alkyl)-2-quinuclidinyl]-4-quinolinemethanol, epimeric in positions a, 2 and 5; and

f. recovering the desired reaction product.

An alternate process comprises:

g. halogenating the product of'step (a) above to yield the corresponding racemic or optically active epimeric 4- {cis or trans 3-[1-acyl-3-vinyl(or lower alkyl)-4- piperidyl]-l-halo-Z-oxopropyl}quinolines;

h. reducing the product of step (g) with subsequent cyclization to yield a mixture of the corresponding racemic or optically active epimeric 4-{cis or trans-3-[1- acyl-3-vinyl(or lower alkyl)-4-piperidyl]-l5,25- oxapropyl quinolines;

i. deacylating the product of step (g) to yield a mixture of the corresponding racemic or optically active 2 epimeric 4-{cis or trans 3-[-3-vinyl(or lower alkyl)-4- piperidyl]-1,2-oxapropyl quinolines;

j. cyclizing the product of step (h) to yield the corresponding racemic or optically active a-[5-vinyl(or lower alkyl)-2-quinuclidinyl]-4-quinolinemethanol epimeric in positions a, 2 and 5; and

k. recovering the desired reaction product.

The end products are useful as antimalarial and antiarrhythmic agents.

In another aspect, the invention relates to a process for preparing racemic or optically active cis or trans lacyl(or l-H)-3-vinyl-4-piperidineacetic acid and esters thereof and racemic or optically active cis or trans lacyl-3-vinyl-4-piperidineacetaldehyde by:

a. nitrosating a racemic or optically active cis or trans 7acyl-decahydro-ZH-pyrido[3,4-d] azepin-Z-one to yield the corresponding racemic or optically active cis or trans 7-acyl-l-nitroso-decahydro-ZH-pyrido[3,4-d] azepin-2-one;

b. pyrrolyzing the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans 1-acyl-3-vinyl-4-piperidineacetic acid; and

c. hydrolyzing, if desired, and esterifying the reaction product of step (b) to yield the corresponding racemic or optically active cis or trans 1-acyl(or l-H)-3-vinyl-4- piperidineacetic acid ester; and

d. reducing and acylating the reaction product of step (c) to yield racemic or optically active cis or trans 1- acyl-3-vinyl-4-piperidineacetaldehyde.

In a further aspect, the invention relates to an alternate process for preparing racemic or optically active cis and trans 1-acyl(or l-l-l)-3-vinyl-4-piperidineacetic acid and esters thereof by:

a. alcoholizing a racemic or optically active cis or trans 7-acyl-decahydro-ZH-pyridol3,4-d] azepin-Z-one to yield the corresponding racemic or optically active cis or trans 1-acyl-3-(2-aminoethyl)-4-piperidineacetic acid esters;

b. methylating the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans l-acyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid esters;

c. oxidizing the reaction product of step (b) to yield the corresponding racemic or optically active cis or trans 1-acyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid ester N-oxide; and

d. pyrolyzing the reaction product of step (c) to yield the desired acetic acid and esters thereof.

In still another aspect, the invention relates to a process for preparing racemic or optically active cis or trans 7-acyldecahydro-2H-pyrido[3,4-d]azepin-2-one which comprises:

a. hydrogenating a racemic or optically active 2acyll,3.4,7,8,8a-hexahydro6(2H)-isoquinolone to yield the corresponding racemic or optically active cis or trans 2-acyloctahydro-6(2H)-isoquinolone; and

b. converting the reaction product of step (a), through a Schmidt Rearrangement, to the corresponding racemic or optically active cis or trans 7-acyldecahydro-2H-pyrido[3,4-dlazepin-2-one.

Alternatively, by a process which comprises:

a. converting, through a Schmidt Rearrangement, a racemic or optically active 2-acyl-l ,3,4,7,8,8a-hexahydro-6(2H)-isoquino|one to the corresponding racemic or optically active 2-acyl-1,2,3,4,7,8,9,9a-octahydro- 6H-pyrido[3,4-d]azepin-6-one; and

b. hydrogenating the reaction product of step (a) to yield the corresponding racemic or optically active cis or trans 7-acyldecahydro-2I-l-pyrido[3,4-dlazepin- 2-one.

In yet another aspect, the invention relates to novel compounds.

DETAILED DESCRIPTION OF THE INVENTION ferred are chlorine and bromine. The term acyl" denotes lower alkanoyl of 1-7 carbon atoms such as formyl, acetyl, propanoyl, butanoyl, heptanoyl, and the like; ar-lower alkanoyl, preferably phenyl-lower alkanoyl, wherein phenyl may be substituted by one or more lower alkyl, lower alkoxy or halogen groups such as benzoyl and the like. The term aryl means phenyl which may be substituted by one or more lower alkyl, lower alkoxy or halogen groups. The term aralkyl means a hydrocarbon group of 7-12 carbon atoms such as benzyl, phenethyl, phenylpropyl and the like. The term acyloxy means an acyloxy wherein the acyl moiety is as hereinbefore described, for example, lower alkanoyloxy and ar-lower alkanoyloxy.

The process for preparing quinine, quinidine, isomers and derivatives thereof is exemplified by Reaction Scheme la, la. la, lb, lb and lb.

Scheme Ia Compounds of theformula Ia and Ila above are useful as antimalarial and antiarrhythmic agents.

7 In Reaction Scheme Ia, 4-methyl-quinolines of for-. mula X, which are known compounds or are analogs of known compounds readily obtained by known procedures, are condensed with l-acyl (or l-H)-3(R)- vinyl(or lower alkyl)-4(S)-piperidineacetic acid ester of formula lXa, antipode or its racemate which are known compounds, are analogs of known compounds readily obtained by known procedures, or are prepared as hereinafter described, in the presence of a base, for example, sodium hydride, an alkali metal alkoxide such as sodium methoxide, or lithium dialkylamide such as lithium diisopropylamide'to yield 4-{3-[ l-acyl(or 1-H)- 3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2- oxopropyl}quinoline of formula Vllla, antipode or its racemate. The condensation is suitably carried out at room temperature; however, temperatures above or below room temperature may be employed. Preferably, the condensation is conducted at a temperature within the range of about 70 and about 50C. Moreover, the

condensation can be suitably carried out in the presence of an inert organic solvent, for example, a hydrocarbon, such as benzene, hexane and the like, or an ether such as ether, tetrahydrofuran or dioxane, or dimethylformamide or hexam ethylphosphoramide.

The 4-{3-[l-acyl(or l-H)-3(R)-vinyl(or lower alkyl- )-4(S)-piperidyl]-2-oxopropyl }quinoline of formula Vllla, antipode or its racemate is converted to the mixture of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S)- piperidyl]2-hydroxypropyl quinolines of formula VIa, their antipodes or racemates by simultaneous deacylation, if necessary, and reduction. The deacylation and reduction are conveniently effected utilizing a reducing agent, for example, diisobutylaluminum hy- If desired, the compound of formula Vla can be esterified to the corresponding mixture of epimeric 4-{3- [3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-acyloxypropyl}quinolines of formula VIIa, their antipodes or racemates utilizing known procedures, for example, reaction with the corresponding organic acid in the presence of a catalyst, such as boron trifluoride. Alternatively, if desired, the compound of formula Vla can be converted to cis and trans 4-{3-[3(R)-vinyl(or lower alkyl)-4(R)-piperidyl]-prop-lenyl quinolines of formula Va, their antipodes or racemates utilizing a dehydrating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like, in the .presence of an organic base, for example, a tertiary amine such as pyridine, triethylamine and the like, at a temperature within the range of about 0 to about room temperature.

The cyclization of epimeric 4-{3-[3(R)-vinyl(or lower alkyl-4(S)-piperidyl]2-hydroxy(or acyloxy)- propyl}quinolines of formulas VIa and Vlla, their antipodes or racemates, respectively and cis and trans 4- {3-[3(R)-vinyl(or lower alkyl)-4(R)-piperidyl]- prop-l-enyl}quinol ines of formula Va, their antipodes or racemates to 4-{a-[5(R)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(S) and 2(R)-yl]-methyl}quinolines of formulas Illa and Na, their antipodes or its racemate is carried out utilizing a cyclizing agent, for example, an organic acid, such as glacial acetic acid or the like. The cyclization is suitably carried out at room temperature; however, temperatures above or below room temperature may also be employed. It is preferred to employ a temperature within the range of about 25 to about C. Moreover, the cyclization can be conveniently conducted in the presence of an inert'organic solvent, for example, a hydrocarbon such as benzene or toluene, or an ether, such as diethyl ether or tetrahydrofuran.

The hydroxylation of the compounds of formulas Illa and lVa or their racemates to a(R)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula la, its antipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yll-4-quinolinemethanol of formula Ila, its antipode or racemate, respectively, is carried out, for example, in the presence of molecular oxygen and a reducing agent, such as dimethylsulfoxide, pyridine, triphenylphosphine, platinum black, or a trialkylphosphite, such as triethylphosphite, or the like, in a strongly basic solution.

A suitable base for the reaction described above comprises, for example, an alkali metal alkoxide, such as potassium t-butoxide, sodium t-butoxide, sodium isoamylate, sodium methoxide or the like, or an alkali metal amide, such as lithium diisopropylamide, sodium amide or the like. Conveniently, a solvent such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, pyridine, t-butanol, a hydrocarbon such as benzene or toluene, an ether such as tetrahydrofuran, dioxane or the like, or mixtures thereof can be utilized.

A preferred reaction medium comprises a mixture of dimethylsulfoxide and t-butanol in the presence of potassiurn t-butoxide.

wherein R R and m are as previously described and R, is acyl.

In Reaction Scheme la an alternative process for the preparation of compounds of formula Vla is described. 4-Methyl-quinolines of formula X are condensed with l-acyl-3(R)-vinyl-(or lowewr alkyl)-4(S)- 'piperidineacetaldehyde of formula XXIlla, its antipode or racemate which are new compounds and are prepared as hereinafterdescribed, in the presence of base, for example, sodium hydride, an alkali metal alkoxide such as sodium methoxide, or lithium dialkylamide such as lithium diisopropylamide to yield the mixture of epimeric 4-{3-[l-acyl-3(R)-vinyl-(or lower alkyl)- 4(S)-piperidyl]-2-hydroxypropyl quinolines of formula XXIVa, their antipodes or racemates. The compounds of formula XXIVa are deacylated to the corresponding mixture of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S )-piperidyll-ZE-hydroxypropyl} quinolines of formula Vla, their antipodes or racemates, utilizing a deacylating agent, for example, alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, a reductive deacylating agent such as lithium aluminum hydride, sodium aluminum hydride, diisobutyl aluminum hydride and the like. Preferably, the deacylation is suitably carried out at room temperature; however, temperatures above and below room temperature may be employed. Moreover, the deacylation can be suitably carried out in the presence of an inert organic solvent for example, a lower alkanol, such as methanol or ethanol, or an ether, such as tetrahydrofuran'or dioxane.

Sch eme 1a (R I) (R l) m \N VIIIa N XXa (R 1) {HQ Q \N XXIa \N XXIIa succinimide, N-bromoacetamide and the like. The halogenation can be conducted in an inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a halogenated hydrocarbon such as carbon tetrachloride; an ether such as diethylether, tetrahydrofuran, dioxane and the like. Conveniently, the reaction can be initiated by a free radical catalyst such as dibenzoylperoxide or by irradiation with infrared. The temperature is not critical, however, it is preferred to conduct. the reaction at a temperature in the range of about room temperature and the reflux temperature of the reaction mixture.

The conversion of the epimeric compounds of formula XXa, their antipod es or racemates to the corresponding mixture of diastereomeric 4-{3-[ l-acyl-3(R)- vinyl(or lower alkyl)-4(S)-piper-idyl]-1,2- oxapropyl}quinolines of the formula XXIa, their antipodes or racemates can be effected utilizing a reducing agent, for example, alkali metal hydrides such as sodium borohydride, potassium borohydride, lithium tritertiarybutoxyaluminum hydride and the like. The reduction is conveniently effected in an inert organic sol vent, for example, aliphatic alcohols such as methanol, ethanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like, at a temperature in the range of about 70C. and about the reflux temperature of the reaction mixture,

The conversion of-the compound of formula XXIa to the corresponding mixture of the diasteromeric 4-{3- [3(R)-vinyl(or lower alkyl)-4(S)-piperidyl]-l,2- oxopropyl}quinolines of the formula XXlla, their antipodes or racemates is effected using a deacylating agent, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxide, or a reducing deacylating agent, for example, dialkylaluminium hydride such as diisobutylaluminum hydride, or an alkali metal The conversion of the compounds of formula XXlla to the corresponding mixture comprising a(R)-[5(R)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula la, its antipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol of formula Ila, its antipode or racemate is effected by reaction with a weak organic or inorganic protonic acid, for example, water, ammonium chloride, lower alkanols such as methanol, ethanol and the like, Lewis acids such as aluminum oxide, aluminum chloride, boron trifluoride and the like. Conveniently, conversion is conducted in the presence of an inert organic solvent, for example, carbon disulfide, hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as dichloromethane, carbontetrachloride, chloroform and the like, and ethers such as diethylether, tetrahydrofuran, dioxane and the like. The temperature of the reaction is not critical. Conveniently, it may be in the range of about 0C. and about the reflux temperature of the reaction mixture.

SchemeIb (iHs 000R;

(R2 Na qaH (Rom IXb VIIIb NH iq-gr-r J J l l a l a o 011 olLRf.

( om (R0111 \NV N VIb VIIb (Rom l (111).

wherein R R R R R and m are as previously de:

scribed The hereinafter described reaction steps of Reaction Scheme lb are effected utilizing the procedures and conditions set forth in Scheme la. The 4-methylquinoline of formula X is condensed with l-acyl(or ll-l)-3(S)-vinyl(or lower alkyl)-4(S)-piperidineacetic acid ester of formula lXb, its antipode or racemate to yield 4-{3-[ l-acyl(or l-H)-3(S)-vinyl(or lower alkyl)- 4(S)-piperidyl]-2-oxopropyl quinoline of formula Vlllb, its antipode or racemate. The compound of formula Vlllb is deacylated, if necessary, and reduced to the mixture of epimeric 4-{3-[3(S )-vinyl(or lower alkyl)-4(S)-piperidyl]-2- hydroxypropyl}quinolines of formula VIb, their antipodes or racemates. If desired, the compounds of formula VIb can be est erified to the mixture of epimeric 4-{3-[3(S )-vinyl(or lower alkyl)-4(S)- piperidyl]-2-acyloxypropyl}quinolines of formula VIIb, their antipodes or racemates or, alternatively, it can be converted to cis and trans 4-{3-[3(S)-vinyl(or lower alkyl)-4(R)-piperidyl]-prop- 1-enyl}quinolines of formula Vb, their antipodes or racemates. The compounds of formula Vb, VIb or VIIb are cyclized to 4-{a- [5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(S) and 2(R)-yl]-methyl}quinolines of formulas lllb and Nb,

their antipodes or racemates. The compounds of formulas Illb and Nb are hydroxylated to a-(R)-[5(S)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula lb, its antipode or racemate and 01(8) -[5(S)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yll-4-quinolinemethanol of formula llc, its antipode or racemate, respectively.

Scheme Ib CHO R: H

X XXIIIb XXIVb ulhereinR R R' and m are as previously described wil h e afte .dessritisqfiaq ism sm 2832919 1 a ss fiflw ut lizi g thiiaresedqrssang XXmb, t a"tt qqserle emetel et fls 29 pounds and are prepared as hereinafter described, to y d the mi tu e of epimeric. 4:15 mews); vinyl(or lower alkyl-4(S)-piperidyll-ZE-hydroxypropyl- }quinolines of formula XXIVb, their antipodes or raceates. The com ounds of formula XXIVb are deac 15 m p y compound such as selenium dioxide, ruthenium tetroxlat to rei29ndinsflmi tur v B iCr [3(S)-vinyl(or lower alkyl)-4(S)-piperidyl]-2-hydroxypropyl}quinolines of formula Vlb, their antipodes or racemates. s. v7

The hydroxylation of the compound of Formulas llla,b-lVa,b to the end products-of Formulas la,b-Ila,b, i.e.,

Mam

can also be effected utilizing molecular oxygen and a catalyst such as platinum, tri s(triphenylphosphine)rhodium chloride or the like or by oxidation utilizing a ide, passadium acetate, mercuric acetate, thallium triacetate, manganese dioxide, cerium (IV) oxide, or the like.

Alternate procedures for the conversion of the compounds of Formula VIa,b to the corresponding compound of Formula llla,bIVa,b are exemplified in Reac- V -tion Scheme V.

IIIa, b-IVu, b

The conversion of compounds Vla,b to the correconversion ofthe 4-{3-[l-acyl-3(S)-vinyl(or lower alksponding compounds of formula XXXl is effected utiyl)-4(S)-pipe ridyl]-2-oxopropyl }quinoline of formula lizing a chloroformate such as benzylchloroformate. Vlllb', its antipode or racemate to the corresponding The compounds of formula XXXl are converted to the mixture of epimeric 4-{3-[ l-acyl-3(S)-vinyl(or lower compounds of formula XXXll by tosylation with a 5 aIkyl)-4(S)-piperidyl]-l-halo-Z-oxopropyl}quinolines compound such as p-toluenesulfonylchloride or p-tolof formula XXb, their antipodes or racemates, respecuenesulfonic acid anhydride in a solvent such as pyritively, is effected utilizing a halogen agent such as N- dine. The conversion of the compounds of formula bromo-succinimide, N-chloro-succinimide, N-

XXXll to the corresponding compound of formula bromoacetamide and the like.The halogenation can be XXXlll is effected by ,the removal of the N- 10 conducted in an inert organic solvent, for example, a carbobenzoxy group utilizing, f r l acetic hydrocarbon such as benzene, toluene and the like. a acid/hydrogen bromide mixture. The cyclization of the ERE??? hydrocarbon Such as Carbon tetrachloride; Compounds of formula Xxxm to corresponding an ether such as diethylether, tetrahydrofuran, dioxane mp u of fQFmUlEI 1S effected y tand the like. Conveniently, the reaction can be initiated mg m an organllc Solvent Such as methanol, ethanol, 5 by a free radical catalyst such as dibenzoylperoxide or methylformamlde, dimethylsulfoxide and t e l by irradiation with infrared The temperature is not Scheme Ib" Ra H R3 H g\/ 1'; IE1

(Rom J (R1)m J (a) N/ I \N/ VIIIb' XXb Ra R1 H i H, H /g\/ (@V H 1'1 NW 0W (R9111 1)m J N I I XXIb XXIlb wherein R R R'.,, m and X are as previously de- 5 critical, however, it is preferred to conductthe reaction scribed. at a temperature in the range of about room temperan Riag onnsg lr ture and the reflux temperature of the reaction mixthe comet's??? of ggmpoufids of formula Ymb' me l lie conversion of the epimeric compounds of for compounds of for n 1 ulas lb and [lb is described The mula XXb, their antipodespr racemates to the correspending mixture of diastereomeric 4-{3-[I-acyl- 3(S I vinyl(or lower alkyl)-4(S)-piper-idyl]-15,25- oxapropyl}quinolines of the formula XXIb, their antipodes or racemates can be effected utilizing a reducing agent, for example, alkali metal hydrides such as sodium borohydricle, potassium borohydride, lithium tritertiarybutoxyaluminum hydride and the like. The reduction is conveniently effected in an inert organic solvent, for example, aliphatic alcohols such as methanol, ethanol and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like, at a temperature in the range of about 70C. and about the reflux temperature of the reaction mixture.

The conversion of the compound of formula XXIb to the corresponding mixture of the diastereomeric 4-{3- [3(S)-vinyl(or lower oxapropoyl}quinolines of the formula XXIIb, their antipodes or racemates is effected using a deacylating agent, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxide, or a reducing deacylating agent, for example, dialkylaluminum hydride such as diisobutylaluminum hydride, or an alkali metal aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride and the like. The deacylation is conveniently conducted in the presence of anf inert organic solvent, for example, Ioweralkanols such as methanol, ethanol and the like, hydrocarbons such as toluene and the like, ethers such as diethylether, tet-.

rahyclrofuran and the like. The deacylation temperature is not critical. Conveniently, it may be in the range of about 70C. to about the reflux temperature of the reaction mixture.

The conversion of the compounds of formula XXIIb to the. corresponding mixture comprising ot(R)-[5(S)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]- 4quinolinemethanol of formula lb, its antipode or racemate and a(S)-[5(S)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(R)-yll-4-quinolinemethanol of formula llb, its antipode or racemate is effected by reaction with a weak organic or inorganic protonic acid, for example, water, ammonium chloride, lower alkanols such as methanol, ethanol and the like, Lewis acids such as aluminum oxide, aluminum chloride, boron trifluoride and the like. Conveniently, conversion is conducted in the presence of an inert organic solvent, for example, carbon disulfide, hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as dichloromethane, carbontetrachloride, chloroform and the like, and ethers such as diethylether, tetrahydro-1 furan, dioxane and the like. The temperature of the reaction is not critical. Conveniently, it may be in the range ofo about 0C. and about the reflux temperature of the reaction mixture.

The various other process aspects of the invention are exemplified by the following reaction schemes Ila, llb, Illa, "lb and IV.

SCHEME Ha.

coon /COOR3 T H f H L H H N N l RI XIIIn 0/\R5 IXo wherein R and R are as previously described, and

R is lower alkyl, aryl or ar-lower alkyl.

In Reaction Scheme Ila, the conversion of 7-acyldecahydro-2H-pyrido[3(R),4(S)-d]azepin-2-one of formula Xla, its antipode or racemate to 7-acyl-I- nitroso-decahydro-2H-pyrido[3(R),4(S)-d]-azepin- 2-one of formula XIIa, its antipode or racemate, respectively, is carried out utilizing a nitrosating agent, such as, for example, sodium nitrite or dinitrogen tetroxide. Conveniently, the reaction can be conducted in the presence of a solvent, for example, an organic acid such as acetic acid, or a chlorinated hydrocarbon such as carbon tetrachloride. The nitrosation is conveniently conducted at a temperature within the range of about 0C. to about room temperature, preferably at The compound of formula XlIa is converted to lacyl-3(R)-vinyl-4(S)-piperidineacetic acid of formula XIIIa, its antipode or racemate, respectively, by pyrolysis. Conveniently, the pyrolysis is conducted at a temperature within the range of about room temperature to about 200C, preferably at a temperature within the range of about C. to about C. Conveniently,

a high boiling solvent such as xylene, decaline and the like, can be utilized in the reaction.

The compound of formula XIIIa is converted to lacyl(or I-H)-3(R)-vinyl-4(S)-piperidineacetic acid ester of formula IXc, its antipode or racemate, respec: tively, utilizing an esterifying agent, for example, a lower alkanol, such as methanol, ethanol, propanol and the like, in the presence of, for example, an inorganic acid such as hydrochloric acid, sulfuric acid and the like. When R is hydrogen, however, the esterification is preceded by hydrolysis in the presence of, for example, an aqueous inorganic acid, such as hydrochloric acid, riaasid an halike- Compounds of formula Xla, wherein R is alkyl, for instance, ethyl, can be prepared as described in Scheme IV.

Scheme 11b XIIb COOH

XIIIb IXd wherein R R, and R are as previously described.

In a like manner, in Reaction Scheme llb, the converaminoethyl)-4(S)-piperidineacetic acid ester of formula XlVa, its antipode or racemate, respectively, utilizing an alcoholizing agent, for example, a lower alkanol such as methanol, ethanol, propanol and the like, in the presence of, for example, anhydrous inorganic acid such as hydrochloric acid, sulfuric acid and the like. Conveniently, the alcoholysis is conducted at a temperature within the range of about room temperataure to about the boiling point of the alkanol.

The compound of formula XlVa is converted to 1- acyl-3(R)-(2-dimethylaminoethyl)-4(S)- piperidineacetic acid ester of formula XVa, its antipode or racemate, respectively, utilizing a methylating sion of 7-acyl-decahydr0-2 -py l agent such as, for example, formic acid/formaldehyde d]azepin-2-one of Formula Xlb, its antipode or race- 5 mixture or for-maldehyde/Raney nickel. The N- mate to 7-acyl-l-nitroso-decahydro-ZH- methylation is conveniently conducted at a temperapyrido[3(S),4(S)-d]azepin-2-one of Formula Xllb, its ture within the range of about room temperature to antipode or racemate, respectively, is carried out. The about the boiling point of the methylating agent. compound of Formula Xllb is converted to l-acyl- The compound of formula XVa is converted to l- 3(S)-vinyl-4(S)-piperidineacetic acid of Formula acyl-3(R)-(2-dimethylaminoethyl)-4(S)- XIllb, its antipode or racemate, respectively, by pyrolypiperidineacetic acid ester N-oxide of formula XVla, sis. The compound of Formula Xlllb is converted to 1- its antipode or racemate, respectively, utilizing an oxiacyl(or ll-H)-3(S)-vinyl-4(S)-piperidineacetic acid dizing agent, fo ex p y g PerOXide Of a P ester of Formula IXd, its antipode or racemate, respecorganic acid such as, peracetic acid. The oxidation is tively. conveniently conducted in the presence of a solvent, for example, lower alkanol, such as methanol, ethanol, Scheme Ina propanol and the like, or a hydrocarbon such as ben- 000R, zene and the like. The oxidation is conveniently conducted at a temperature within the range of about 0 to about room temperature, preferably at 0C. NH: The compound of formula XVIa is converted to 1- acyl(or 1-l-l)-3(R)-vinyl-4(S)-piperidineacetic acid ester of formula lXc, its antipode or racemate, respec- N/ tively, by pyrolysis. Such pyrolysis is conveniently conducted at a temperature in the range of about 80 to about 200C, preferably at a temperature within the range of about 90 to about 125C. When R is hydro- XIVa gen, however, the pyrolysis is followed by hydrolysis and reesterification. 000R; COOR;

H Scheme IIIb COORa 2 N CH 2 N(CH:) L( a) l o II L It VNH: 2: 0 Re N l XVa XVIa XIvb 00034 H\( H(CH3)2 l H 0 R4 L IX(c) N wherein R R andli are as previously described.

XVI)

ln Reaction Scheme llli, 7-acyl-decahydro-2H- pyrido[3(R),-4(S)-d]azepin-2-one of formula Xla, its antipode or racemate is converted to l-acyl-3(R)-(2- IXd wherein R R and R are as previously described.

In a like manner, in Reaction Scheme lIIb, 7-acyldecahydro-2H-pyrido[3(S),4(S )-d]azepin-2-one of Formula Xlb, its antipode or racemate is converted to l-acyl-3(S)-(2-aminoethyl)-4(S)-piperidineacetic acid ester of Formula XIVb, its antipode or racemate, respectively. The compound of Formula XIVb is converted to l-acyl-3(S)-(Z-dimethylaminoethyl)-4(S)- piperidineacetic acid ester of Formula XVb, its antipode or racemate, respectively. The compound of Formula XVb is converted to l-acyl-3(S)-(2- dimethylaminoethyl)-4(S)-piperidineacetic acid ester N-oxide of Formula SVIb, its antipode or racemate, respectively. The compound of Formula XVIb is converted to I l-acyl(or l-H)-3(S)-vinyl-4(S)- piperidineacetic acid ester of Formula IXd, its antipode or racemate.

SCHEME IV a. .QEYl IL wherein R is as previously described.

In the Reaction Scheme IV, racemic 2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone of formula XVII is converted to the racemic cis and trans Z-acyloctahydro-6(2I-I)-isoquinolones of formula XVllla and XVIIIb, respectively, utilizing a hydrogenating agent, for example, hydrogen in the presence of palladium or rhodium catalyst. Conveniently, the hydrogenation can be conducted in the presence ofa solvent, for example, a lower alkanol such as methanol, ethanol, propanol and the like, with or without an inorganic acid such as hydrohalic acid, for example, hydrochloric acid and the like. The hydrogenation can be conveniently con ducted at a temperature within the range of about room temperature and about 50C.

The racemates of the compounds of formula XVllla or XVIIIb are resolved to the corresponding optical antipodes by conventional methods which are further illustrated by Examples 3, 4, 5.

The conversion of 2-acyl-4a(S),8a(R)-octahydro- 6(2I-I)-isoquinolone of formula XVIIIa, its antipode or racemate to 7-acyldecahydro-2I-I-pyrido[3(R),4(S)- d]azepin-2-one of formula Xla, its antipode or racemate, respectively, is carried out utilizing the known Schmidt rearrangement, i.e., the reaction of the compound of formula XVIIIa with sodium azide in the presence of an inorganic acid such as sulfuric acid or polyphosphoric acid, with or without solvent, at a temperature within the range of from about 0 to about C. In a like manner, 2-acyl-4a(S).8a(S)-octahydro-6(2I-I)- isoquinolene of Formula XVIIIb, its antipode or racemate is converted to 7-acyl-decahydro-2H- pyrido[3(S),4(S)-d]azepin-2-one of Formula Xlb, its antipode or racemate, respectively.

The racemic compound of Formula XVII is con- In another aspect, the invention relates to the compounds of formulas lb, IIb, IIIb, IVb, Va, Vb, VIa, VIb, VIIa, 'VIIb, VIIIa, VIIIb, IXb, Xla, Xlb, XIIa, XIIb, Xlllb, XIVa, XIVb, XVa, XVb, XVIa, XVIb, and XIX.

The compounds of formulas lb and IIb are useful as antimalarial and antiarrhythmic agents; all the other compounds listed in the above paragraph are useful intermediates.

In still another aspect, the invention relates to compounds of the formulas IIIc and l H R1 IVO wherein n is 0 t0 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoro IVd I. TRZI l I) H I 1'1 CI-IaO- A CHaO J N and \N/ wherein R is methyl or C -C lower alkyl, their antipodes and racemates.

Compounds of formulas lllc, llld, [V and lVd are useful intermediates.

In still another aspect, the invention relates to compounds of the formulas IVe wherein n is 0 to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, halogen, or when n is 2, R taken together with an adjacent R is also methylenedi oxy; when R is hydrogen, R is C -C alkoxy, lower alkyl, trifluoromethyl or halogen, when R is other than hydrogen and n is 1, R is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl, halogen, or taken together with an adjacent R is meth-l ylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen and their antipodes and racemates.

As is evident from the above R or R or the like are individually selected from the various groupings hereinbefore described. Moreover, when m or n is 2, R or R, or the like can additionally form with an adjacentv R, or R or the like the methylenedioxy radical. Thus, either when m or n is 1 or 2, R or R or the like can individually also represent hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or trifluoromethyl. Additionally, when m or n is 2, two adjacent groupings of R or R, can together represent methylenedioxy.

In yet another aspect, the invention relates to compounds of the formulas wherein R is methyl or C -C lower alkyl, their antipodes and racemates. Compounds of formulas llle, lllf, We and IVf are useful intermediates.

In a further aspect, the invention relates to compounds of the formulas wherein n is 0 to 2; R is vinyl or lower alkyl; R is hydrogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl or halogen, and when n is 2, R taken together with an adjacent R is also methylenedioxy; when R is hydrogen, R is C -C alkoxy, lower alkyl, trifluoromethyl or halogen; when R is other than hydrogen and n is l,R is lower alkoxy, lower alkyl, hydrogen, trifluoromethyl or halogen, or taken together with an adjacent R is methylenedioxy; and when R is other than hydrogen and n is 2, R is hydrogen, and their antipodes and racemates, and pharmaceutically acceptable acid addition salts.

Exemplary of the compounds of formulas lc and He are:

6,8-dimethoxy-a(R)-[5(S)-ethyl-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6,8-dimethoxy-3-epi-dihydrocinchonidine] its antipode and racemic analog;

7-chloro-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol [hereinafter referred to as 7'- chloro-3-epidihydrocinchonidine] its antipode and racemic analog;

6,7-methylenedioxy-a(R)-[5(S)-ethyl-4(S)- quinuclidin-2(S)-yll-4-quinolinemethanol [hereinafter referred to as 6',7-methylenedioxy-3-epi- -dihydrocinchonidine] its antipode and racemic analog;

7-trifluoromethyl-a(R)-[5(S)-ethyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 7-trifluoromethyl-3-epidihydrocinchonidine] its antipode and racemic analog; 6,8-dimethoxy-a(S)-[5(S)-ethyl-4(S)-quinuclindin- 2(R)-yll-4-quinolinemethanol [hereinafter referred to as 6',8'-dimethoxy-3-epi-dihydrocinchonine] its antipode and racemic analog;

7-chloro-a(S)-[5(S)-ethyl-4(S)-quinuclindin-2(R)- yll-4-quinolinemethanol [hereinafter referred to as 7- chloro-3-epi-dihydrocinchonine] its antipode and racemic analog;

6,7-methylenedioxy-a(3H5(S)-ethyl-4(S)- quinuclindin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6',7-methylenedioxy-3-epidihydrocinchonine] its antipode and racemic analog;

7-trifluoromethyl-a(S)-[5(S)-ethyl-4(S)- quinuclidin-2(R)-yl]-4-quinolinemethanol [hereianfter referred to as 7-trifluoromethyl-3-epidihydrocinchonine] its antipode and racemic analog.

Aslo included in the purview of the invention are tipodes and racemates and pharmaceutically acceptable acid addition salts.

Also included in'the purview of the invention are compounds of the formula:

The antipode of 6-methoxy-a(R)-[5(S)-ethyl-4(S)- quinuclidin-2(S)-yl]-4-quinolinemethanol [hereinafter referred to as 6-methoxy-3-epi-dihydrocinchonidine or 3-epi-dihydroquinine] and its racemic analog (Compound A) and The antipode of 6-methoxy-a(S)-[5(S)-ethyl-4(S)-' quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as 6-methoxy-3-epi-dihydrocinchonine or 3-epi-dihydroquinidine] and its racemic analog (Compound B). The compounds of formulas Ic, Id, He and lld, as well as Compounds A and B, are useful also as antimalarial and antiarrhythmic agents.

The compounds of the formula IXa have demonstrated cardiovascular activity, such as, hypotensive ac-' tivity. The pharmacologically useful cardiovasulcar activity is demonstrated in warm-blooded animals utilizing standard procedures, For example, the test compound is administered to anesthetized mg/kg sodium pentobarbital), artificially respired (Palmer Pump) dogs. Femoral arterial blood pressure and respiratory resistance (measured in terms of pressure) are recorded on a direct writing oscillographic recorder. A series of control responses of the blood pressure and respiration are obtained and duplicated. The control procedures used are: intravenously administered norepinephrine (l y/kg), histamine (1 'y/kg), serotonin (25 'y/kg) and hypertensin (0.5 y/kg), as well as the' bilaterial occulsion of the carotid arteries and the electrical stimulation of the central portion of a severed vagus nerve (SV, c.p.s., 10 sec.). Each of the control procedures is administered at 5-minute intervals. Five minutes after the series of control responses, the drug to be tested is intravenously administered and its effects recorded. The series of control procedures is repeated after dosing to determine the effect of the compound on these standard responses. If the control responses are unaltered by the test drug, a second compound is administered and the procedure repeated. If the test compound alters the blood pressure or the control responses, the control procedures are repeated at convenient intervals until the animal has returned to its predose status or a new physiological status is established.

When meroquinene-t-butylester d-monotartrate of the formula 5 is utilized as the fe st substance at a dose of4 mg/kg. in-

travenously, the following results are obtained:

blood pressure 25 for 35 minutes serotonin Central Vagus Stimulation slight inhibition Carotid Occlusion blocking Hypertension N.E. Norepinephrine slight inhibition Histamine slight inhibition The compounds of Formula IXa also exhibit antiestrogenic activity. This useful estrogenic activity is demonstrated in warm-blooded animals. For example, the test compound is administered once daily for three consecutive days to groups of ten (10) immature female rats (40-50 grams). On the first treatment day, all rats are injected subcutaneously with 0.25 meg. estradiol in sesame oil. On the fourth day, uteri are removed as autopsy and weighed on a torsion balance.

When meroquinene-t-butylester d-monotartrate is utilized as the test substance at a dosage of 1 mg/kg. p.o., an 1 1 percent antiestrogen inhibition is observed with a 12 percent uterine change.

The compounds of formulas la, Ila, lb and 11b, including compounds of the formulas lc, Id, He and Ild, as well as compounds A and B, and their pharmaceutically acceptable acid addition salts possess antimalarial and antiarrhythmic properties and are therefore useful as anti-. malarial and antiarrhythmic agents. Their pharmacologically useful antiarrhythmic activity is demonstrated in warm-blooded animals utilizing standard procedures, for example, the test compound is administerred to prepared mongrel dogs. The chest cavity of the experimental animal previously anesthetized using a combination of sodium barbitol, 300 mg/kg. and pentobarbitol, 15 mg/kg., i.e., is opened up through the third right interspace under artificial-respiration and the pericardium is cut and sutured to the wall of the thorax so as to maintain the heart in a pericardial cradle throughout the course of the test procedure. Arterial pressure is monitored by inserting a polyethylene cannula into the aorta via the left carotid artery and is measured with an appropriate Statham pressure transducer. During the course of the experiment, electrical activity of the heart is viewed both on an oscilloscope and recorded on a Sanborn polyviso using ECG lead ll. The heart is also observed visually. The antiarrhythmic assay of the test drug is undertaken using a modification of the method of Scherf and Chick, 1951. A dripping of 1 percent solution of acetylcholine is applied to the sinus node and the atrium is irritated by pinching witin a pair of forceps. This procedure produces a continuous artiral arrhythmia which mostly consists of atrial fibrillation. Since hypokalemia produces an susceptibility t'o atrial fibrillation (Leveque, 1964), 2 units/kg. of insulin is administered 30 minutes before the start of the quetyleheline drip. Once atrial fibrillation is established, there is a 10-minute waiting period before the test drag is adminitered. The test drugs are administered at the rate of l mg/kg/minute until normal sinus rhythm appears or until 30 mg/kg. of drug is administered.

When 6'-methoxy-a(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yl]-4-quinoline methanol is utilized as the test substance at a dosage of about 4.0 mg/kg, an antifibrillatory effect is observed for more than 60 minutes.

Their pharmacological useful antimalarial activity is demonstrated in warm-blooded animals using standard procedures, for example, the test substance is administered to albino mice in variable amounts. Albino mice are inoculated with about -10 million red cells infected with P. Bergei. Treatment is started on the first day after inoculation, and the drug is administered per os during 4 consecutive days. On the 7th day of infection, smears are made, stained with giemsa and microscopically examined for P. Bergie.

When racemic 7-methoxy-dihydrocinchonidine dihydrochloride or racemic 7-methoxydihydrocinchonine dihydrochloride is utilized as the test substance at dosages in the range of 125 mg/kg. to about 250 mg/kg., the microscopical examination of the blood smears is free of P. Berghei (negative). When 6'-methoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol [dihydroquinine] or 6- methoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin- 2(S)-yl]-4-quinolinemethanol is utilized as the test substance at a dose of about 200 mg/kg, the microscopical examination of the blood smears is free of P. Berghei (negative). The compounds of formulas la, lla, lb and llb, including the compounds of formulas [0, Id, llc and lld, as well as compounds A and B, and their pharmaceutically acceptable acid addition salts have effects qualitatively similar, for example, to those of quinine and quinidine, known for their therapeutic uses and properties. Thus, the compounds of the invention demonstrate a pattern of activity associated with antimalarials and antiarrhythmics of known efficacy and safety.

Furthermore, the compounds of the formulas la, lla,' lb and llb, including the compounds of formulas Ic, Id, llc and lld, as well as compounds A and B, can be utilized as flavoring agents in beverages in the same manner as quinine is now used for this purpose.

The compounds of formulas Ia, lla, lb and llb, including the compounds of formulas lc, ld, llc and lld, as well as compounds A and B, form acid addition salts and such salts are also within the scope of this invention. Thus, the compounds of formulas la, lIa, lb and llb, including the compounds of formulas lc, ld, lie and lid, as well ascompounds A and B, form pharmaceutically acceptable addition salts with, for example, both pharmaceutically acceptable addition salts with, for example, both pharmaceutically acceptable organic and inorganic acids, such as acetic acid, succinic acid, formic acid, methanesulfonic acid, p-toluene-sulfonic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and the like.

The products of the invention can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral or parenteral application with the usual pharmaceutical adjuvant materials, e.g., organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols, and their like. The pharmaceutical preparations can be employed in a solid form, e.g., as tablets, troches, suppositories, capsules, or in liquid form, e.g., as solutions, suspensions or emulsions. The pharmaceutical adjuvant 10 material can include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. They can also contain other therapeutically active materials.

The quantity of active medicament which is present in any of the above-described dosage forms is variable. The frequency with which any such dosage form will be administered will vary, depending upon the quantity of active medicament present therein, and the needs and requirements of the pharmacological situation.

Due to the possible different spatial arrangements of their atoms, it is to be understood that the compounds of this invention may be obtained in more than one possible stereoisomeric form. The novel compounds, as described and claimed, are intended to embrace all such isomeric forms. Accordingly, the examples included herein are to be understood as illustrative of particular mixtures of isomers or single isomers and not as limitations upon the scope of the invention. All temperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of racemic cis 2-benzoyl-octahydro- 6(2H)-isoquinolone from racemic 2-benzoyl- 1,3 ,4,7,8,8a-hexahydro-6( 2l-l)-isoquinolone To a solution containing 151 g. of racemic 2-benzoyll,3,4,7,8,8a-hexahydro-6(2l-l)-isoquinolone in 3000 ml. of absolute ethanol were added 300 ml. of 3N aqueous hydrochloric acid and 30 g. of 5 percent rhodium on alumina catalyst. The mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogenceased. The catalyst was removed by filtration and washed thoroughly with ethanol. The filtrate was partially evaporated in vacuo, diluted with 3500 ml. of dichloromethane and washed with 3N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and sodium chloride solutions. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to yield a crystalline product. Gas chromatographic analysis indicated that it contained 61.9 percent of racemic cis 2-benzoyloctahydro-6(2H)-isoquinolone and 13 percent of racemic trans 2-benzoyl-octahydro-6(2H)-isoquinolone. The product was recrystallized twice from benzene to give racemic cis 2-benzoyl-octahydro-6(2H)- isoquinolone having a melting point of l47148.5.

EXAMPLE 2 Preparation of racemic trans 2-benzoyl-octahydro- 6(2H)-isoquinolone from racemic 2-benzoy1- l,3,4,7,8,8a-hexahydro-6( 2H)-isoquinoline To a solution containing 25.5 g. of racemic 2- benzoyl-l ,3',4,7,8,8a-hexahydro-6(2H)-isoquinolone in 1000 ml. of percent ethanol were added 2.5 g of 10 percent palladium on carbon catalyst and the mixture was hydrogenated at room temperature and 3 atmospheres pressure until the uptake of hydrogen ceased.

The catalyst was removed by filtration and washed with 95 percent ethanoland dichloromethane. The filtrate was evaporated to dryness to yield an oil which crystallized on trituration with ether. the product was recrystallized twice from absolute ethanol to yield racemic trans 2-benzoyl-octahydro-6(2l-l)-isoquinolone, which after two additional recrystallizations from absolute ethanol, had a melting point of l57.5l59.

EXAMPLE 3 Preparation of 2-benzoyl-4(R).5(R)-dimethyl-l', 2, 3, 4, 4'a(S),7, 8, 8a(S)-octahydrospiro[1,3-dioxolane-2,6'(5H)-isoquinoline] and 2-benzoyl- 4(R),5(R)-dimethyl-l', 2', 3, 4, 4'a(R), 7', 8, 8a (R)-octahydrospiro[ l ,3-dioxolane-2,6'(5'H)- isoquinoline] To a solution containing 23.4 g. of rac. trans-2- benzoyloctahydro-6( ll-l)-isquinolone in 2 l. of anhydrous benzene was added 2.24 g. of p-toluenesulfonic acid and 9.83 g. of ()-butane-2(R),3(R)-diol. The resulting solution was refluxed for 3 hours and the water which formed was collected in a water separator. After the addition of 18 ml. of pyridine, the mixture was diluted to 4 l. with benzene, washed four times with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The last traces of pyridine were removed by codistillation with toluene in vacuo. The crystalline residue,.29.62 g., was fractionally crystallized byrepeating several times the follow- 30 in g system 29.62 g. mixture of ketals 6 hours reflux with distilled petroleum ether (b.p. 3060 C.)

insoluble part soluble part recrystallization recrystallization from ether from ethanol-water 1:1

2-Benzoyl-4(R),5(R)-dimethyl-l', 2', 3, 4', 4'a(S),7, 8', 8a(S)-octahydrospiro[1,3-dioxolane- 2,6(H)-isoquin0line] m.p. l47 l48.5, [M 9.95 (c 1.005, CH OH).

2-Benzoyl-4(R),5(R)-dimethyl-l, 2, 3', 4, 4'a(R),7, 8', 8'a(R)-octahydrospiro[1,3-dioxolane- 2,6-(5H).-isoquinoline] had a melting point of l82l84; [04],, 875 (c 0.96, CH OH).

EXAMPLE 4 4a(S),8a(S )-2-benzoyloctahydroand three times with ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield 2 g. of 4a(S),8a(S)-2-benzoyloctahydro-6(2H)- isoquinolone, having a melting point of 15 l-l53 (from absolute ethanol); [01],, 6l.8 (c 1.01. CHCIH).

EXAMPLE 5 Preparation of 4a( R ),8a( R )-2-benzoyloctahydro- 6(2H)-isoquinolone A solution containing 0.329 g. of 2-benzoyloctahydro-6(2H)-isoquinolone having a melting point of 15 l-l53 (from absolute ethanol); [a] -62.60 (c 1.005, CHCl EXAMPLE 6 Preparation of racemic cis 7-benzoyl-decahydro-2H- l pyrido[3,4-d]-azepin-2-one from racemic cis 2- benzoyl-octahydro-6( 21-1 )-isoquinolone To a suspension containing 20.6 g. of finely ground racemic cis 2-benzoyl-octahydro-6(2H)-isoquinolone in 800 g. of polyphosphoric acid were added 10.0 g. of sodium azide, and the mixture was stirred 16 hours at 5566. After cooling at room temperature, the reaction mixture was poured onto crushed ice. The resulting solution was made alkaline with solid soduim carbonate at 0, and was extracted thoroughly with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The oily residue crystallized on trituration with acetone. Fractional crystallization of the crystalline product from acetone yielded cis 7-benzoyldecahydro-2H-pyrido[3,4-dlazepin-2-one, which after one recrystallization from absolute ethanol and three recrystallizations from acetone had a melting point of l67l68.5.

EXAMPLE 7 Preparation of racemic trans 7-benzoyl-decahydro-2H- pyrido[3,4-dl-azepin-2-one from racemic trans 2- benzoyl-octahydro-6(2H)-isoquinolone To a mixture containing 5.15 g. of trans 2-benzolyoctahydro-6(2H)-isoquinolone and 200 g. of polyphosphoric acid were added 2.5 g. of sodium azide and the reaction mixture was stirred at 5560 for 16 hours. After cooling to room temperature, the polyphosphoric acid was hydrolyzed by addition of ice. The resulting solution was made alkaline with concentrated sodium carbonate solution and extracted thoroughly with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield 5.45 g. of crystalline racemic trans 7- benzoyl-decahydro-2H-pyrido[3,4-dl-azepin-2-one. After recrystallization from ethanol/ether it had a melting point of l87l89.

EXAMPLE 8 Preparation of a (S),9a(S)-7-benzoyldecahydro-2l-lpyrido[3,4-d] azepin-2-one To a mixture of finely ground 2.57 g. of 4a(S),8a(S)- 2-benzoyloctahydro-6(2H)-isoquinolone and 100 g. of polyphosphoric acid was added 1.3 g. of sodium azide. The reaction mixture was stirred at 5560C. (bath) for 16 hours, cooled to room temperature and poured into ca. 380 g. of crushed ice. After the ice had melted, the resulting solution was made alkaline with 6N aqueous sodium carbonate (370 ml.) and extracted 3 times with 300 ml. of methylene chloride. Methylene chloride extract was washed 3 times with ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness, to give 2.72 g. of crystalline 5a(S),9a(S)-7- benzoyldecahydro-2H-pyrido[3,4-d]azepin-2-one. From absolute ethanol it crystallized with one mole of ethanol, m.p. 200-203C., [01],, 37.83 (c. 1.0547, CHCI on drying loses ethanol to give anhydrous form, m.p. 90100.

EXAMPLE 9 temperature. ice was added. The resulting solution was made alkaline with saturated aqueous sodium carbonate at 0 and was extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The product was crystallized by trituration with acetone to give racemic 2-benzoyl-l,2,3,4,7,8,9,9aoctahydro-6H-pyrido[3,4-d]azepin-6-one having a melting point of 2l9221.

EXAMPLE 10 Preparation of racemic cis 7-benzoyl-decahydro-2H- pyride[3,4-dl-azepin-2-one from racemic Z-benzoyl- 1,2,3,4,7,8,9a-0ctahydr0-6H-pyrido[3,4-d]azepin- 6-one To a solution containing 5.4 g. of racemic 2-benzoyl- 1,2,3,4,7,8,9,9a-0ctahydr0-6H-pyrido[3,4-d]azepin- 6-one in 450 ml. of absolute ethanol were added 10 ml. of 3N aqueous hydrochloric acid and 5.4 g. of Spercent rhodium on alumina catalyst. The reaction mixture was hydrogenated at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Thereafter, the catalyst was removed by filtration and washed thoroughly with ethanol. The filtrate was neutralized with 2N aqueous sodium carbonate and evaporated to a small volume in vacuo. The residue was extracted with 1000 ml. of dichloromethane. The extract was washed with water, dried with anhydrous sodium sulfate and evaporated to dryness. The non-crystalline product exhibited an lR-spectrum identical to that of the racemic cis 7-benzoyl-decahydro-2H-pyrido[3,4- d]azepin-Z-one of Example 6, and after being recrystalaminoethyl)-4-piperidine-acetic acid ethyl ester from racemic cis 7-benzoyl-decahydro-2H-pyrido[3,4- d]azepin-2-one A solution containing 2.8 g. of racemic cis 7-benzoyldecahydro-2H.-pyrido[3,4-d]azepin-2-one in 500 ml. of Spercent othanolic hydrochloric acid was refluxed for hours. Thereafter, the solvent was removed by evaporation in vacuo. The residue was taken up in 1,200 ml. of dichloromethane. The resulting solution was shaken with a solution containing 0.53 g. of sodium carbonate in 10 ml. of water, dried over anhydrous sodium sulfate and evaporated to yield oily racemic cis l-benzoyl-3-( 2-aminoethyl)-4-piperidineacetic acid ethyl ester.

EXAMPLE 12 Preparation of racemic trans 1-benzoyl-3-(2- aminoethyl)-4-piperidinecetic acid ethyl ester from racemic trans 7-benzoyl-decahydro-2H-pyrido[3,4-

A solution containing 2.0 g. of racemic trans 7- benzoyl-decahydro-2l-l-pyridol3,4-d1azepin-2-one in 350 ml. of Spercent ethanolic hydrogen chloride was refluxed for 65 hours. After the solvent was removed in vacuo, the residue was dissolved in water, made alkaline with 2N aqueous sodium carbonate and evaporated to dryness in vacuo. The residue thus obtained was extracted with boiling dichloromethane. The extract was separated from inorganic salts by filtration and evaporated to dryness to yield racemic trans lbenzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester.

EXAMPLE 13 Preparation of racemic cis 1-benzoyl-3-vinyl-4- piperidineacetic acid ethyl ester (racemic N- benzoylmeroquinone ethyl ester) from racemic cis lbenzoyl-3-(2-aminoethyl )-4-piperidineacetic acid ethyl ester A mixture containing 1.91 g. of racemic cis 1- benzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester, 1.38 g. of formic acid and 1.05 g. of 37percent formaldehyde was heated for 1 hour at 100. After cooling to room temperature, 3.5 ml. of concentrated hydrochloric acid were added and the mixture thus obtained was evaporated to dryness in vacuo. The residue was dissolved in 50 ml. of water. The solution was washed by shaking with ether, made alkaline to about a pH 8 with 2N sodium carbonate and extracted thoroughly with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give oily racemic cis 1-benzoyl-3-(2-dimethylarninoethyl)-4- piperidineacetic acid ethyl ester. To the stirred solution containing this product in 10 m1. of methanol were added 2 ml. of 30percent aqueous hydrogen peroxide at 0. The reaction mixture was warmed to room temperature and stirred for 16 hours. The excess of hydrogen peroxide was decomposed by addition of platinum black with stirring for 1 hour at The platinum black was separated by filtration and washed with methanol. The filtrate was evaporated to dryness in vacuo to yield racemic .cis l-benzoyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid ethyl ester N-oxide as an oil. Heating of this product in vacuo at a temperature from 90 to 125C. over a period of 25 minutes yielded racemic N-benzoylmeroquino'ne ethyl ester, which, after purification by preparative thin layer chromatography and recrystallization from hexane, had a melting point of 66-68.

EXAMPLE 14 Preparation of racemic trans 1-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester from racemic trans l-benzoyl-3-(2-aminoethyl)- i -piperidineacetic acid ethyl ester A mixture containing 1.4 g. of racemic trans lbenzoyl-3-(2-aminoethyl)-4-piperidineacetic acid ethyl ester, 1.4 g. of formic acid and 1.1 g. of 37 percent aqueous formaldehyde was heated at 95100. The reaction mixture became a clear solution and a vigorous evolution of gas occurred, which ceased after 1.5 hours. After cooling to room temperature, 1 ml. of concentrated hydrochloric acid was added and the mixture was evaporated in vacuo. The residue was dissolved in 100 ml. of water, washed by shaking with ether, made alkaline with 2N aqueous sodium carbonate and extracted thoroughly with dichloromethane. The extract was dried-over anhydrous sodium sulfate and evaporated to yield racemic trans 1-benzoyl-3-(2- dimethylaminoethyl)-4-piperidine acetic acid ethyl ester.

EXAMPLE Preparation of racemic trans l-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide from racemic trans 1-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester To a stirred solution containing 0.73 g. of racemic trans 1-benzoyl-3-(Z-dimethylaminoethyl)-4- piperidineacetic acid ethyl ester in 10 ml. of methanol was added 1 ml. of 30 percent hydrogen peroxide at 0. The reaction mixture was allowed to warm to room temperature and was then stirred overnight. The excess of hydrogen peroxide was decomposed by stirring with platinum black for 2 hours at 0C. The platinum black was removed by filtration and the filtrate evaporated to dryness yielding racemic trans 1-benzoyl-3-(2- dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide.

EXAMPLE 16 W Preparation of racemic trans 1-benzoyl-3-vinyl-4- piperidineacetic acid ethyl ester from racemic trans lbenzoyl-3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide.

A flask containing 0.63 g. of racemic trans l-benzoyl- 3-(Z-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide was pyrolyzed at 90-l20 for 20 minutes. The product was chromatographed on a 400 g. silica gel column with ether to yield racemic trans 1- benzoyl-3-vinyl-4-piperidineacetic acid ethyl ester as a glass. 7 w LL 1 Preparation of racemic cis 7-benzoyl-l-nitrosodecahydro-2H-pyrido[3,4-k1azepin-2-one from racemic cis 7-benzoyl-decahydro-2H-pyrido[3,4-dlazepin- 2-one To a solution containing 5.521 g. of nitrogen tetroxide in 360 ml. of carbon-tetrachloride at were added 9.84 g. of anhydrous sodium acetate. The mixture was allowed to warm to 0 and a solution containing 10.88 g. of racemic cis 7-benzoyl-decahydro-2H-pyrido[3,4- d]azepin-2-one in 40 ml. of dichloromethane was added with stirring. After 30 minutes at 0, the mixture was poured into a slurry of ice and water. The resulting mixture was placed in a separatory funnel and the organic phase was separated. The aqueous phase was extracted thoroughly with ice-cold dichloromethane. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness at 0C. in vacuo to yield oily racemic cis 7- benzoyl-1-nitroso-decahydro-2H-pyridol3,4-d1- azepin-2-one.

EXAMPLE 18 Preparation of racemic trans 7-benzoyl-1-nitrosodecahydro-2H-pyrido[3,4-d]azepin-2-one from racemic trans 7-benzoyl-decahydro2H-pyrido[3,4- d]azepin-Z-one To ml. of carbontetrachloride solution containing g. of nitrogentetroxide at 70 were added 2.46 g. of anhydrous sodium acetate. The mixture was allowed to warm to 0, and 2.6 g. of racemic trans 7-benzoyldecahydro-2H-pyrido[3,4-dl-azepin-2-one in 50 ml. of dichloromethane were added with stirring. The reaction mixture was maintained at 0 for 30 minutes. Thereafter, it was poured into a slurry of ice and water, transferred to a separatory funnel and the organic phase was removed. The aqueous phase was extracted with three 250 ml. portions of dichloromethane. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield racemic trans 7 benzoyl-l-nitrodecahydro-2H-pyrido[3,4-d]azepin-2one, a green yellow powder. Alloperations were carried out at 0.

EXAMPLE 19 Preparation of racemic N-benzoyl-meroquinene [racemic cis 1-benzoyl-3-vinyl-4-piperidineacetic acid]from racemic cis 7-benzoyl-l-nitroso-decahydro-2H- pyrido[3,4-d1azepin-2-one v The racemic cis 7-benzoyl-l-nitroso-decahydro-2l-lpyrido-[3,4-dlazepin-2-one from Example 17 was placed in a flask fitted with a reflux condenser and heated under nitrogen on an oil bath maintained at for about 1 hour. The residue was taken up in 50 ml. of 1N potassium hydroxide, diluted with 50 ml. of water and washed by shaking with ether. The aqueous phase was neutralized with 50 ml. of 1N hydrochloric acid and extracted with ether. The ether phase was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to yield racemic N- benzoyl-meroquinene, as an oil.

EXAMPLE 20 Preparation of racemic trans l-benzoyl-3-vinyl-4- piperidineacetic acid from racemic trans 7-benzoyl-lnitroso-decahydro-ZH-pyrido-[3,4-d1azepin-2-one The product of Example 18, i.e., racemic trans 7- benzoyl-1-nitroso-decahydro-2H-pyrido[3 ,4-d]azepin- 2-one was heated at 125 under nitrogen for 1 hour. The product was taken up in 13 ml. of 1N aqueous potassium hydroxide and 30 ml. of water, washed with four 100 ml. portions of ether, neutralized with 13 ml. of 1N aqueous hydrochloric acid and extracted with four 200 ml. portions of ether. The ethereal extract was washed with 70 ml. of water, which has combined with aqueous phase, dried over anhydrous magnesium sulfate and evaporaated to yield oily racemic trans 1- benzoyl-3-vinyl-4-piperidineacetic acid.

EXAMPLE 21 Preparation of piperidineacetic acid To 143 ml. of 0.15M solution of dinitrogen tetroxide in carbontetrachloride immersed in a dry ice-acetone bath were added 3.51 g. of anhydrous sodium acetate, and the mixture was allowed to warm to C. A solution containing 3.86 g. of 511 (S), 9a(S)-7- benzoyldecahydro-ZH-pyrido[3,4-d1azepin-2-one in 50 ml. of methylene chloride was added with stirring,

and after standing for 30 minutes at 20C. the mixture was poured into a slurry of ice and water (280 ml.). The resulting mixture was placed in a separatory funnel and the organic phase was removed. The aqueous phase was extracted 3 times with 430 ml. of methylene chloride. The combined organic phases were washed with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo. All these operations were carried out at 0C. It gave quantitative yield of pale yellow powder, 1-nitroso-5a(S), 9a(S)-7-benzoyldecahydro-2H-pyrido[3,4-d]azepin-2-one, which was processed immediately further.

The nitroso product was heated at 125C. (bath) under nitrogen. Initially violent reaction ceased slowly after 30 minutes. The residue (3.92 g.) was taken up in 19 ml. of 1N aqueous potassium hydroxide, diluted with water (60 ml.) and washed 4 times with 150 ml. of ether. [t was then neutralized with 19 ml. of 1N aqueous hydrochloric acid and extracted 4 times with 300 ml. of ether. The ethereal extract was washed with 60 ml. of water, dried over anhydrous magnesium sulfate and evaporated invacuo to give 2.34 g. of oily 1- benzoyl-3(S)-vinyl-4(S)-piperidineacetic acid which contained minor impurities (tlc).

EXAMPLE 22 Preparation of racemic N-benzoylmeroquinene methyl ester [racemic cis 1-benzoyl-3-vinyl-4-piperidineacetic acid methyl esterlfrom racemic N- benzoylmeroquinene [racemic cis 1-benzoyl-3-vinyl-4- piperidineacetic acid] To a stirred solution containing 5.29 g. of racemic N- benzoylmeroquinene in 500 ml. of ether was added 1 g. of diazomethane in 50 ml. of ether. Stirring was continued for minutes. The excess diazomethane was 36 decomposed by a dropwise addition of glacial acetic acid until the yellow color disappeared. The reaction mixture was diluted to 1,000 ml. with ether, washed with 2N sodium carbonate and water, dried over anhy-- drous magnesium sulfate and evaporated in vacuo to yield oily N-benzoylmeroquinine methyl ester.

EXAMPLE 23 Preparation of 1-benzoyl-3(R)-vinyl-4(S)- piperidineacetaldehyde from 1-benzoyl-3(R)-vinyl- 4(S)-piperidineacetic acid methyl ester To a dry ice cooled solution of 1.48 g. (0.005 mole) of l-benzoyl-3(R)-vinyl-4(S)-piperidineacetic acid methyl esterin 100 ml. of toluene was added dropwise (5min.) with stirring 8 ml. (ca. 0.012 mole) ofa 25 percent solution of diisobutyl aluminum hydride in toluene. Stirring was continued for 30 min. at -78, then 5 ml. of methanol-water (1:1) was added, and stirring at 78 was continued. After min., 0.6 ml. (0.005 mole) of benzoylchloride and 4 g. of solid sodium carbonate was added, the dry ice bath was removed, and the mixture was stirred for 60 min. The inorganic solids were removed by filtration, washed with methanol, and the combined organic phases evaporated to dryness. The crude product was dissolved in ml. of dichloromethane, washed (1 X 1N sodium carbonate. 1 X water), dried (sodium sulfate) and evaporated. The crude product (1.7 g.) was separated by preparative layer chromatography to give 0.235 g. (17.5 percent) of 1- benzoyl-3(R)-vinyl-4(S)-piperidineacetaldehyde as a colorless oil.

EXAMPLE 24 Preparation of rac. trans piperidineacetic acid methyl ester To the solution of 0.476 g. of rac. trans l-benzoyl-3- vinyl-4-piperidineacetic acid in 4 ml. of methanol was added 9 ml. ofdiazomethane solution in ether (concentraton ca. 3 g./ ml.). After few minutes an additional 9 ml. of diazomethane solution was added, and then stirred at room temperature for 1 hour. The excess of diazomethane was destroyed by addition of several drops glacial acetic acid. and thus resulted mixture was evaporated to dryness in vacuo, leaving 0.5 g. of oily residue. The crude product was chromatographed on 7 Brinkman silica gel preparative plates with benzeneether 1:1 mixture. Elution with 95 percent ethanol gave 0.201 g. of oily rac. trans l-benzoyl-3-vinyl-4- piperidineacetic acid methyl ester.

1 -benzoyl-3-vinyl-4- EXAMPLE 25 Preparation of l-benzoyl-3(S)-vinyl-4(S)- piperidineacetic acid methyl ester To a cooled solution containing 2.34 g. of l-benzoyl- 3(S)-vinyl-4(S)-piperidineacetic acid in 20 m1. of methanol was added 20 ml. of diazomethane solution in ether (concentration ca 3 g./130 ml.). After few minutes an additional 20 ml. of diazomethane solution was added and then stirred at room temperature for 5 minutes. The excess of diazomethane was destroyed by addition of several drops of glacial acetic acid, and thus resulted mixture was evaporated to dryness in vacuo,

37 leaving 2.9 g. of oil residue. The crude product was chromatographed on 26Brinkman silica gel preparative plates with benzene-ether 1:1 mixture. Elution with 95 percent ethanol gave 1.059 g. of oily l-benzoyl- 3(S)-vinyl-4(S)-piperidineacetic acid methyl ester, [a] 1.61 (c. 1.1193, CHCl EXAMPLE26 Preparation of racemic cyanomethyl) glutaric acid diethyl. ester To the boiling solution of 37.24 g. of glutaconic acid diethyl ester and 70.08 g. of benzylcyanoacetate in 100 ml. of anhydrous tetrahydrofuran was added dropwise 22.4 g. (0.20 mole) of potassium t-butoxide in 300 ml.-

of anhydrous tetrahydrofuran over a hour-hour period. The reaction mixture was stirred and refluxed for 12 hours. The solvent was removed by distillation in vacuo. To the residue was added 100 ml. of water and extracted with 31. of benzene. The benzene extract was washed four times with 100 ml. of water, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was fractionally distilled to give 42.55 g. of racemic 3-(albenzyloxycarbonylcyanomethyl)glutaric acid diethyl ester, b.p. l67l74 at 0.15 mmHg. Large scale runs average to 61 percent yield.

EXAMPLE27 Preparation of racemic 3-(1-berizy1oxycarbonyl-1- cyanopropyl glutaric acid diethyl ester The mixture of 18 g. 'of racemic 3-(abenzyloxycarbonylcyanomethyl)glutaric acid diethyl ester, 15.6 g. of ethyliodide and 6.72 g. of potassium t-butoxide in 200 ml. of anhydrous tetrahydrofuran was stirred and refluxed for 3 hours, which it became neutral. The precipitate formed during the reaction was separated by filtration and washed with tetrahydrofuran. The combined filtrates were evaporated to dryness, and after addition of 20 ml. of water, extracted with l l. of benzene. The benzene extract was washed 3-(a-benzyloxycarbonyli EXAMZLEZQ Preparation of racemic cis 4-ethoxycarbonylmethyl-5- ethyI-Z-piperidone T and racemic trans 4- ethoxycarbonylmethyl--ethyl-2-piperidone To a solution of 101.23 g. (0.395 mole) of 3-(1- cyanopropyl) glutaric acid diethyl ester in 1200 ml. of absolute ethanol was added 31.8 g. of Raney nickel,

. and hydrogenated at 110 atm and temperature, which with water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was fractionally distilled to give 11.35 g. of racemic 3-(1- benzyloxycarbonyl-1-cyanopropyl)glutaric acid diethyl ester, b.p. 1541599 at 25 microns. Large scale runs average to 70 percent yield.

EXAMPLE 28 Preparation of racemic 3-( l-cyanopropyl)glutaric acid diethyl ester To the solution of 23.4 g. (0.06 mole) of 3-(1- benzyloxycarbonyl-l-cyanopropyl)glutaric acid diethyl ester in 600 ml. of 95 percent ethanol was added 3 g. of 10 percent palladium on carbon, and hydrogenated at room temperature and atmospheric pressure. After uptake of 0.06 mole of hydrogen, the reaction ceased. Catalyst was removed by filtration through celite, and the filtrate was evaporated to dryness. The residue, 2,032 g., was heated at 170180 in vacuo for 1 hour. After cooling to room temperature, it was dissolved in 1 l. of ether. The ethereal solution was washed three times with ml. of concentrated aqueous solution of sodium bicarbonate, and water, driedover anhydrous magnesium sulfate and evaporated to dryness to give 14.17 g. of racemic 3-(1-cyanopr0pyl)glutaric acid diethyl ester, b.p. 84-86 at 20 microns.

in the course of three hours rose slowly from room to 152C. After cooling to room temperature, the catalyst was separated by filtration through celite and the filtrate evaporated to dryness in vacuo. On trituration with ether, 57.6 g.. of racemic trans 4- ethoxycarbonylmethyl-S-ethyl-2-piperidone, m.p. 86-88 was obtained. After one recrystallization from methylene chloride-ether, m.p. was 8991.

The mother liquors were evaporated to give 23.5 g. of oily residue, which was chromatographed on a 2 kg. silica gel column. The elution with ethanol-chloroform mixture' gave 16 g. 'of racemic cis 4- ethoxycarbonylmethyl-S-ethyl-2-piperidone.

EXAMPLE 30 Preparation of racemic trans3-ethyl-4-piperidineacetic acid ethyl ester The solution of 0.640 g. of racemic trans4- ethoxycarbonylmethyl-S-ethyl 2-piperidone and 0.684 g. of triethyloxonium fluoroborate in 20 ml. of anhydrous methylene chloride was stirred at room temperature 65 hours, and then evaporated in vacuo. The crude enolether was dissolved-in 20 ml. of absolute ethanol, the solution was cooled to 0C. and 0.25 g. (0.0066 mole) of sodium borohydride was added in portions. The reaction mixture was stirred for 23 hours at room temperature, then diluted with 50 ml. of water and extracted with 1 1. of methylene chloride. Methylene chloride extract was washed with water (3 X 50 ml.), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in 7 ml. of ice-cold 1N hydrochloric acid, the resulting solution diluted with m1. of water and washed five timesby shaking with 50 ml. of ether. It was then made alkaline with 8 ml. of 1N sodium hydroxide and extracted with 1 l. of methylene chloride. Methylene chloride extract was washed three times with 50 ml. of water, dried over anhydrous sodium sulfate and evaporated to dryness, to give 0.591 g. (99 percent) of racemic trans3-ethyl-4- piperidineacetic acid ethyl ester b.p. 9 1-92 (bath) at 0.5 mmHg.

EXAMPLE 31 Preparation of racemic cis 6-methoxy-4 {3-[1- benzoyl-3-vinyl-4-piperidyl]-2-oxopropyl quinoline from -methoxylepidine and racemic N- benzoylmeroquinene methyl ester [cis l-benzoyl-3- vinyl-4-pipe'ridineacetic acid methyl ester] To a solution containing about 0.032 mole of lithium diisopropyl amide [prepared at 20 in an atmosphere of dry nitrogent by the addition of 6 ml. of dry diisopropylamine to 15.5 ml. of phenyllithium in benzene-ether (7:3)] were added dropwise a solution containing 5.6 g. of 6-methoxylepidine in 60 ml. of anhydrous tetrahydrofuran. The reaction mixture was stirred for 20 minutes. To the practically homogenous, darkbrown solution of 6-m'ethoxylepidyl lithium thus obtained was added dropwise over a period of 20 minutes a solution containing 4.6 g. of racemic N-benzoylmeroquinene methyl ester in 60 ml. of anhydrous tetrahydrofuran. 

1. A COMPOUND OF THE FORMULA
 2. A mixture of compounds in accordance with claim 1, wherein R1 is methoxy; R2 is vinyl and m is 1, i.e., cis and trans 6-methoxy-4-(3-(3(R)-vinyl-4(R)-piperidyl)-prop-1-enyl)quinolines.
 3. A compound of the formula 